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INTRODUCTION — Schizophrenia is a psychiatric disorder involving chronic or recurrent psychosis. It is commonly associated with impairments in social and occupational functioning [1]. It is among the most disabling and economically catastrophic medical disorders, ranked by the World Health Organization as one of the top ten illnesses contributing to the global burden of disease [2].

Antipsychotic medications are first-line medication treatment for schizophrenia. They have been shown in clinical trials to be effective in treating symptoms and behaviors associated with the disorder. Antipsychotic medications have significant side effects; assessment and management of these adverse effects are an important part of treatment. Evidence-based psychosocial interventions in conjunction with pharmacotherapy can help patients achieve recovery.

Pre-treatment assessment — When feasible, patients who are started on an antipsychotic medication should receive a baseline physical examination with a neurological exam. Particular attention should be focused on factors that may be affected adversely by antipsychotic medication: (See "Pharmacotherapy for schizophrenia: Side effect management".)

When feasible, laboratory evaluations should be initiated before starting an antipsychotic. With the exception of patients treated with clozapine, the antipsychotic can usually be started before the results of laboratory tests are available.

●A 2017 clinical trial found cariprazine, a newer antipsychotic, to be efficacious in reducing negative symptoms compared with risperidone [7]. The trial randomly assigned 461 patients with stable schizophrenia and predominant negative symptoms to receive cariprazine or risperidone. After 26 weeks, patients assigned to cariprazine showed a greater mean reduction in negative symptoms on the Positive and Negative Syndrome Scale compared with risperidone-treated patients, with a small to medium effect size. Cariprazine did not have a differential effect on positive symptoms, depression, or EPS, but improved social functioning compared with risperidone.

●A 2015 meta-analysis studied the efficacy of many classes of medications for negative symptoms in 12,318 patients with schizophrenia in 168 randomized trials [6]. Small statistically significant reductions in negative symptoms were found for second-generation antipsychotics, antidepressants, glutamatergic agents, and combinations of these medications, but not for first-generation antipsychotics and brain stimulation. None of the beneficial effects for any of the medication strategies were considered to be of a clinically significant magnitude. (See "Schizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis", section on 'Negative symptoms'.)

Antipsychotic medications are commonly grouped into two categories, with “second-generation” (or “atypical”) applied to clozapine and all antipsychotics first marketed after clozapine was approved in 1989, and “first-generation” applied to antipsychotics marketed previously. Recent clinical research, however, has strongly suggested that the distinction between first- and second-generation antipsychotics has questionable validity and is confusing [5]. The pharmacologic properties, therapeutic effects, and adverse effects are not distinct between and are heterogeneous within the groups. Nevertheless, the terms first- and second-generation antipsychotic are still in widespread use. A valid distinction is that the newer (second-generation) antipsychotics tend to cause fewer extrapyramidal side effects than the older ones, particularly at the high end of approved dosage ranges.

Administration — The dose of most antipsychotic drugs should be titrated from an initial dose to the therapeutic range as quickly as tolerated. Quetiapine, clozapine, and iloperidone need to be increased gradually before reaching a therapeutic dose. The timeframe for titration differs for each drug and also depends on the individual patient’s tolerance of the drug’s tendency to cause sedation and hypotension. In most cases, patients can reach a therapeutic level in five or six days with quetiapine and iloperidone, and two to three weeks with clozapine. Suggested dosing and side effect profiles for each antipsychotic drug are shown in tables (table 1 and table 2).

Because identifying the appropriate dose range can be difficult in the pre-marketing phases of drug development, the antipsychotic doses listed (table 2) deviate somewhat from those approved by the US Food and Drug Administration, reflecting more recent research findings or clinical experience. Examples include:

●Haloperidol is effective and most useful at doses drastically below the FDA-specified maximum of 100 mg/day. Optimal haloperidol dosages are usually below 10 mg/day and almost always below 20 mg/day.

●Optimal dosages of risperidone are lower than the approved 16 mg/day; typically, a maximum dose for risperidone is 6 to 8 mg/day.

Resolution of psychotic symptoms generally occurs over several days and may take as much as four to six weeks. Clinicians should avoid the impulse to change the medication or dose prematurely. Once the dose reaches the therapeutic range, the decision to increase the dose should follow at least several days of treatment during which the individual shows little or no improvement. Higher dosing should be accompanied by careful observation of the patient for side effects. If patients fail to show improvement on doses above the usual therapeutic range, the dose should be reduced.

As an example, a patient treated with risperidone can be started on 2 mg administered as a single daily dose or 1 mg twice a day. If this dose is well tolerated (ie, minimal sedation, hypotension, or akathisia) the dose can be increased to 3 mg on the second day and 4 mg on the third day. Since 4 mg is in the therapeutic range for most patients, the clinician may then choose to continue this dose for an additional two weeks before considering an increase. If the patient shows only minimal or no improvement, the dose can be increased up to 8 mg daily with careful monitoring for clinical response and side effects. Doses of risperidone above 8 mg daily are associated with substantial risk of EPS.

Because of dose-related toxicities, antipsychotics should be used at the lowest dose that is effective for an individual. The toxicities of antipsychotic drugs typically increase with higher doses while therapeutic effects can reach a maximum. At high doses, the adverse effects of an antipsychotic may surpass the marginal benefit of dosage increases. As a result, increasing the dose of antipsychotic for a patient who is already experiencing significant EPS is unlikely to result in additional symptom reduction [8-10].

Course of response — When a patient with schizophrenia is administered an antipsychotic medication, the initial response is often a side effect such as sedation, restlessness, or postural hypotension. It is important to explain this to patients, or they may conclude that the medication is ineffective or worsening their condition. Most patients who will improve on an antipsychotic show the most rapid improvement in the first two weeks [11]. Although the rate of improvement may slow after two weeks, patients will often continue to improve during subsequent weeks and months.

During the first weeks of treatment, patients may first experience a decrease in the severity of symptoms. As a result, the impact of symptoms on patient behavior may be reduced [12]. Hallucinations or delusions may be less frightening or the patient may find that they can distract themselves by focusing their attention elsewhere [13]. Delusions that are based on misinterpretations from an earlier time may linger, whereas the tendency to misinterpret new information may be reduced.

POOR RESPONSE TO INITIAL TREATMENT — Patients should be observed on a stable dose of an antipsychotic for two to six weeks before concluding the drug is ineffective. The duration of the trial will vary depending on a number of factors:

●Although patients improve most rapidly during the first two weeks, they may continue to improve for several weeks or even months on a stable dose [11].

●However, recent evidence suggests that if patients show only a minimal response to an antipsychotic drug during the first two weeks, it is unlikely that the individual will have a robust response [14]. The 2009 Schizophrenia PORT recommends that trials last for two to six weeks. This timeframe will be slightly longer for antipsychotics such as iloperidone and quetiapine, which require slow titration.

Dose adjustments — In cases of nonresponse or partial response, the antipsychotic dose can be gradually increased toward the high end of the recommended range (table 2).

Most careful studies of doses above the recommended range have not found higher doses to be more effective than the maximal recommended dose [15,16]. If used, trials of higher doses should be time limited, with reassessment planned within three months. Unless clear evidence of improvement is seen, high doses should not be continued [17].

A dose reduction can be helpful in cases where side effects, such as akathisia, parkinsonism, sedation, or insomnia have obscured the benefit of a higher antipsychotic dose, or have been mistaken for signs of ineffective treatment, such as agitation or negative symptoms.

Changing to another antipsychotic — Switching antipsychotics can be helpful when a poor response is related to side effects. As an example, in the large US effectiveness study of antipsychotic treatment for schizophrenia, the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE), patients who gained weight during the first phase of antipsychotic treatment frequently lost weight when they were changed to ziprasidone, an antipsychotic that is not associated with weight gain [18].

Switching antipsychotics is less clearly beneficial when the initial medication lacked effectiveness. Most studies have shown that poor responders to one antipsychotic are likely to be poor responders to another antipsychotic except when the second agent is clozapine. (See 'Treatment-resistant schizophrenia' below.)

As an example, an analysis of patients who were on olanzapine, quetiapine, or risperidone prior to the CATIE trial showed that the patients on olanzapine or risperidone who were randomly assigned to continue the same antipsychotic had better outcomes than patients who were randomly assigned to change antipsychotics [19].

●A standard cross-titration for a stable patient: Simultaneous taper of the current medication with titration of the replacement drug in three to four steps over several days to several weeks.

●For patients at higher risk of relapse, the current medication is maintained at its full dose as the new medication is increased. Once the second drug has reached its target dose, the first medication may be gradually decreased and discontinued. In most cases this change can be managed in one to two weeks.

Discontinuation of antipsychotic medications is generally well tolerated, except for clozapine, for which both cholinergic rebound and withdrawal-emergent movement disorders have been reported [22-24]. A slow taper of clozapine over one to two weeks is recommended. Chlorpromazine and thioridazine can also cause cholinergic rebound and should be reduced over a week or more.

Adding a second antipsychotic — Clinicians often add a second antipsychotic when patients have a suboptimal response to a single drug. Little empirical evidence supports this practice [25]. Although some randomized trials indicated that augmentation of clozapine with another antipsychotic may have some benefit, a meta-analysis of this practice found the supporting evidence to be weak [26].

Persistent suicidality — Clozapine has been shown in randomized trials to reduce suicide attempts in patients with schizophrenia and schizoaffective disorder at high risk for suicide [27]. A patient with schizophrenia who has persistent suicidal ideation warranting clinician concern may benefit from a trial of clozapine. Guidelines for clozapine prescribing, dosing, monitoring, and side-effect management are described separately. Management of suicidal patients is described separately. (See "Guidelines for prescribing clozapine in schizophrenia" and "Suicidal ideation and behavior in adults".)

Acutely agitated — Clinical management of the acutely agitated patient with schizophrenia is a common objective on inpatient units and other settings. Agitation can be defined as a state characterized by motor restlessness, excitement, and mental tension.

Treatment of agitation in patients with schizophrenia should be guided by the cause, which can include extrapyramidal symptoms (EPS), substance use, or psychosis:

●Extrapyramidal symptoms — Akathisia can be difficult to distinguish from psychotic agitation when patients are unable to describe the experience of restlessness [28]. Akathisia can be treated with a benzodiazepine; eg, lorazepam can be started at 0.5 mg orally twice daily and incrementally increased to a maximum of 6 to 10 mg/day.

●Psychosis — Psychotic symptoms of schizophrenia, such as frightening delusions, suspiciousness, and command hallucinations can cause patients to become agitated. The agitation associated with psychosis can be treated with an antipsychotic or an antipsychotic combined with a benzodiazepine. The selection of a drug and the route of administration depend on a number of considerations including the urgency of calming the patient and the cooperativeness of the patient [30]. As noted below, the choice of an antipsychotic depends on the formulation selected. It is important to note that the treatment goal is to induce a calmer state, which can often be accomplished without inducing sedation.

●Standard oral formulations: Although many clinicians tend to favor sedating antipsychotics for agitated patients, non-sedating agents can also be effective for reducing agitation. Risperidone 1 to 2 mg or olanzapine 5 to 10 mg will usually be effective in these circumstances.

●Oral rapidly dissolving formulations: Oral rapidly dissolving formulations are available for risperidone, olanzapine, asenapine, and aripiprazole. These formulations are helpful when a patient is willing to take a pill by mouth, but either cannot or does not swallow it. Dosing for these formulations is the same as for standard oral formulations, eg, risperidone 1 to 2 mg or olanzapine 5 to 10 mg.

●Short-acting intramuscular (IM) injectable formulations (eg, haloperidol, olanzapine, aripiprazole, and ziprasidone): Olanzapine 5 or 10 mg administered intramuscularly is a good choice under most circumstances. IM haloperidol is effective but should be given with benztropine or diphenhydramine to reduce the risk of severe EPS including dystonias.

•We advise against the use of IM chlorpromazine, which can induce severe postural hypotension.

•Akathisia from any IM antipsychotic can contribute to agitation.

•Injectable IM antipsychotics have two potential advantages over oral antipsychotics. First, they can be administered safely to uncooperative individuals. Second, patients reach an effective plasma concentration sooner than with oral formulations. For example, patients may experience a calming effect within 10 to 30 minutes following IM administration. Calming effects may take 30 to 60 minutes following oral administration.

Although repeat administration of an oral or intramuscular antipsychotic is common when the prior dose does not sufficiently reduce agitation, the overall antipsychotic dose should be limited, because these medications can cause significant side effects such as hypotension, EPS, and sedation, particularly at high doses over a brief period of time [11]. Maximum antipsychotic doses are shown in a table (table 3).

To limit the amount of antipsychotic used, most physicians either start with a combination of an antipsychotic and benzodiazepine or use a benzodiazepine when patients fail to respond to one or two doses of an antipsychotic for agitation. Lorazepam can be administered as 1 to 2 mg orally or 0.5 to 1 mg intramuscularly for calming.

First-episode psychosis — Patients in a first psychotic episode tend to have higher response rates than patients who have experienced multiple psychotic episodes. These individuals also respond to lower antipsychotic doses [3]. At the same time, younger patients and first episode patients have a greater vulnerability to side effects such as weight gain and extrapyramidal side effects (EPS) [31]. Since many first episode patients are also reluctant to take an antipsychotic, it is important to minimize adverse effects.

The Schizophrenia Patient Outcomes Research Team (PORT) recommended treating first episodes with antipsychotics other than clozapine or olanzapine. Both of these medications are associated with more weight gain, insulin resistance and dyslipidemia than other antipsychotics [3]. In addition, clozapine can cause agranulocytosis.

The Schizophrenia PORT recommended that first-episode patients receive antipsychotic doses in the lower half of the recommended dose range [3]. As examples, a first-episode patient would be treated with 1 to 3 mg of risperidone or 10 mg of aripiprazole daily. An exception to this recommendation should be made for quetiapine, which may require titration to 500 to 600 mg daily.

MAINTENANCE PHASE — Patients with schizophrenia who have recovered from an acute psychotic episode will usually reach a stable or maintenance phase in which psychotic symptoms are reasonably well controlled. The goal of maintenance antipsychotic treatment of schizophrenia is to minimize symptoms and functional impairments, avoid relapses, and promote recovery that allows self-determination, full integration into society, and pursuit of personal goals.

Efficacy of antipsychotic medication — For patients with schizophrenia who have recovered from an acute psychotic episode, we suggest that antipsychotic medication should be continued indefinitely, even for patients who have achieved remission from a first psychotic episode. This suggestion is in accordance with the recommendation of the Schizophrenia PORT [3]. The lowest effective dose that achieves therapeutic goals should be used. Patients should participate in the clinical decision-making regarding the duration of antipsychotic drug treatment.

Multiple randomized trials have found that maintenance antipsychotic medication reduces the risk of relapse over a period of up to two years. A meta-analysis of 6493 patients with schizophrenia in 65 randomized trials of 7 to 12 months duration found that patients who continued on an antipsychotic experienced a lower relapse rate compared to patients withdrawn from an antipsychotic and receiving placebo (27 versus 64 percent; number needed to treat to benefit = 3, 95% CI 2–3) [32]. Other studies of up to two years have found similar results [33].

A seven-year follow-up assessment of patients randomly assigned to either a dose reduction strategy or to maintenance antipsychotic treatment found results that conflict with the studies of up to two years. Two reports that follow describe an intervention and follow-up assessment of patients who experienced a first episode of psychosis and subsequently met criteria for remission prior to enrollment in the trial [34,35].

●The initial trial randomly assigned 128 patients to continue maintenance treatment or to a dose reduction strategy [34]. After two years, patients assigned to the dose reduction strategy had a higher rate of relapse, without offsetting advantages, compared to patients continuing on maintenance treatment.

●A subsequent assessment at seven years follow-up included 103 of the 128 patients (81 percent) who participated in the trial [35]. Patients who had originally been assigned to the dose reduction strategy experienced a higher rate of recovery (ie, symptomatic and functional remission) compared to patients originally assigned to maintenance treatment.

More studies of longer term outcomes of maintenance treatment versus dose reduction are needed before we would suggest an approach other than indefinite continuation of maintenance treatment for patients with schizophrenia following an acute episode of psychosis.

As these trials demonstrate, some people with schizophrenia do well without continuous antipsychotic treatment; however, they are not identifiable prospectively [36].

Other considerations regarding selection of antipsychotic medication for maintenance treatment mirror those for pharmacotherapy during the acute phase. (See 'Drug efficacy' above.)

Cognitive impairment — Improving cognitive impairment has increasingly become an objective of treatment for schizophrenia. Preliminary studies suggest that antipsychotic medication may improve cognition when received early in the course of schizophrenia [37,38]. Studies of patients with chronic schizophrenia have generally found less improvement in cognition during antipsychotic treatment [38-41]. Trials of other medications (including n-methyl-d-aspartate (NMDA) glutamatergic receptor agonists, glycine, D-serine, ampakine CX516, D-cycloserine, donepezil, rivastigmine, and galantamine) have failed to show significant benefit [42-50].

Comorbid disorders — Depressive disorders and anxiety disorders can be challenging to diagnose in patients with schizophrenia. A primary comorbid disorder needs to be distinguished from symptoms of schizophrenia, antipsychotic drug side effects, and other clinical presentations. Properly diagnosed, however, these syndromes can respond to antidepressant and anxiolytic medications [51]. (See "Depression in schizophrenia" and "Anxiety in schizophrenia".)

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●For patients with schizophrenia who have recovered from an acute psychotic episode, we suggest that antipsychotic medication should be continued indefinitely at the lowest effective dose that achieves therapeutic goals (Grade 2C). This approach is suggested even for patients who have achieved remission from a first psychotic episode. (See 'Maintenance phase' above.)

●The selection of which antipsychotic medication to use for an individual patient with schizophrenia should be made based on patient clinical factors and the side effect profiles of antipsychotic drugs. With the exception of clozapine for patients with refractory symptoms, there is not convincing evidence to favor one antipsychotic over the others based on efficacy. (See 'Drug efficacy' above.)

•Because olanzapine is associated with significant weight gain and metabolic adverse effects, leading guidelines state that it should not be used as a first-line agent for first-episode patients, but should be considered for patients who fail treatment with a first-line agent.

●Other strategies for the patient with schizophrenia who has not adequately responded to an antipsychotic drug include:

•Changing to another antipsychotic has been shown to be an effective strategy for addressing side effect problems but is not clearly associated with improved efficacy, with the exception of clozapine. (See 'Changing to another antipsychotic' above.)

•Adding a second antipsychotic medication has not been proven efficacious in randomized trials. For patients with psychotic symptoms that do not respond to two trials of antipsychotic monotherapy, a trial of clozapine is strongly recommended before combining two antipsychotics. (See 'Adding a second antipsychotic' above.)

●Hospitalized patients with schizophrenia may require treatment for agitation. If agitation is associated with psychotic symptoms of schizophrenia, it can be treated with a standard oral formulation, rapid dissolving, or intramuscularly injected antipsychotic, depending on the level of patient participation. Other causes of agitation should be ruled out, including akathisia and substance abuse or withdrawal. (See 'Acutely agitated' above.)